Reviews & Analysis

Protein ubiquitylation has important regulatory functions, influencing protein–protein interactions and protein stability. The final step of ubiquitylation is catalysed by ubiquitin ligases (E3s), a diverse group of proteins that operate with distinct mechanisms. Recent structural data have provided insights into these mechanisms, extending our understanding of E3 function and regulation.

Vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) are crucial for the formation and remodelling of blood vessels. VEGFR2, which is the main endothelial VEGFR, is regulated by receptor-interacting proteins, endocytosis and trafficking. Recent insights have been gained into these layers of regulation and the crosstalk between VEGFR2 signalling and other endothelial signalling cascades.

Encounters and conflicts between the transcription and replication machineries are common and represent a major intrinsic source of genome instability. Recent data shed new light on the biological relevance of transcription–replication conflicts and the factors and mechanisms involved in either preventing or resolving them.

The role of epigenetic regulation in adult stem cell function depends on the specific tissue and factor, but it commonly affects stem cell maintenance, self-renewal and differentiation without disrupting germ-layer fate.

Selective autophagy pathways engage selective autophagy receptors (SARs) that identify and bind to cellular cargoes (proteins or organelles) destined for degradation. Recent yeast studies have provided insights into the regulation and mechanisms underlying SAR function. As these mechanisms are conserved from yeast to mammals, it is now possible to formulate general principles of how selectivity during autophagy is achieved.

CRISPR–Cas9-based genome editing tools have been developed recently to study non-coding transcriptional regulatory elements, enabling the characterization of enhancers in their endogenous context. The applications, current limitations and future development of such CRISPR–Cas9 tools are discussed, with emphasis on identifying and characterizing enhancer elements in a high-throughput manner.

Tight junctions are barriers between epithelial and endothelial cells that regulate the diffusion of molecules across tissues; they also contribute to cell polarity and serve as signalling platforms. Recent findings have broadened our understanding of tight junction organization, assembly and function.

When animal cells divide, they undergo dramatic changes in shape, polarity and mechanical properties. At mitotic entry, the remodelling of cortical actomyosin and cell–substrate adhesions, combined with osmotic swelling enable cell rounding, which is then reversed as cells exit mitosis. We now have a better understanding of the regulation of such shape changes and how they contribute to accurate segregation of chromosomes and other cellular components.

Recent structural, biochemical and single-molecule biophysical studies have elucidated the molecular mechanisms underlying the control of SNARE (solubleN-ethylmaleimide-sensitive factor attachment protein receptor) complex assembly and disassembly by chaperones.

Rho GTPases, which cycle between a GTP-bound active form and a GDP-bound inactive form, regulate cytoskeletal and cell adhesion dynamics and thus are crucial for the coordination of cell migration, cell polarity and cell cycle progression. Rho GTPases and their regulators (GEFs, GAPs and GDIs) are also regulated by post-translational modifications and the formation of regulatory complexes to ensure precise spatiotemporal Rho GTPase activation.

RNA helicases can either remodel or lock the composition of messenger ribonucleoprotein complexes, and thus they have pleiotropic functions in the regulation of gene expression. RNA helicases can drive the progression of mRNAs between various RNA-processing factories, leading to protein synthesis or to mRNA storage or decay.

Embryonic, brown adipocytes, together with beige, brown-like adipocytes induced in white fat depots in response to various stimuli, constitute specialized heat-producing fat cells that contribute to organismal energy expenditure. Important insights have now been gained into the transcriptional and epigenetic regulation of biogenesis and thermogenesis of these cells, opening up new possibilities for the treatment of metabolic disorders.

Many proteins that canonically function in the cytosol can also localize to the nucleus. The authors propose that a distinct group of such proteins (which they name STRaNDs) engage in a particular mode of signal transduction, whereby in response to extracellular cues, the cytosolic protein transits to the nucleus and regulates gene expression without direct DNA binding.

Signalling by ubiquitin, SUMO and other ubiquitin-like modifiers (UBLs), and crosstalk between these modifications, underlies cellular responses to DNA double-strand breaks (DSBs). Important insights have been gained into the mechanisms by which ubiquitin and UBLs regulate protein interactions at DSB sites to enable accurate repair in mammalian cells, thereby protecting genome integrity.

Double-strand break (DSB) repair at telomeres — the ends of linear chromosomes — can cause chromosome end fusions and genomic instability, which drives tumorigenesis. As several mechanisms protect mammalian telomeres from the DNA damage response, telomeres have emerged as a system to uncover key steps in DSB repair.

Proteins of the Fanconi anaemia pathway are master regulators of genomic integrity through their interactions with other DNA repair pathways to repair interstrand crosslinks, stabilize replication forks and regulate cytokinesis.

To celebrate almost 50 years from the discovery of tubulin, six eminent researchers reflect on how the field of microtubule research has advanced over the past five decades, discuss impacts on clinical translation, and provide their thoughts on what key questions need to be addressed in the near future.

Ribonucleotides are incorporated into DNA by various mechanisms, including by DNA polymerases during replication. Such ribonucleotides may have physiological functions, but their presence is typically associated with diverse structural aberrations and interferes with fundamental processes, including DNA replication, repair and transcription. Thus, efficient mechanisms of ribonucleotide removal are key to maintaining genomic integrity and functionality.

Seven transmembrane domain (7TM) receptors are a vast group of proteins that respond to various cues and transmit signals intracellularly by interacting with heterotrimeric G proteins, arrestins and G protein-coupled receptor kinases. Recent structural analyses reveal common means of interaction between 7TM receptors and these intracellular signalling components.

SMC (structural maintenance of chromosomes) complexes are found in all living organisms and include condensin, cohesin and the SMC5–SMC6 complex. Recent mechanistic insight into these ring-shaped protein machines, which topologically encircle DNA, shed light on how they function to mediate chromosome condensation, sister chromatid cohesion and DNA repair.